Clinical features and outcomes of patients with anti-factor H antibody, associated with atypical hemolytic uremic syndrome (aHUS), were reported in a nationwide study conducted by Indian researchers.
The study, “Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database,” was published in the journal Frontiers in Immunology.
aHUS is an autoimmune disease characterized by the progressive destruction of red blood cells due to impaired function of the complement system — a set of more than 50 proteins that forms part of the body’s immune defenses.
Damaged red blood cells are prone to form aggregates, leading to the formation of clots that can clog the kidney’s filtering system, potentially resulting in kidney failure.
Complement regulators are proteins that regulate and prevent complement-mediated damage; one of the most important of these factors is called complement factor H (FH).
Approximately 24% of adults and 19% of children with aHUS in Europe, North America, and Australia produce high amounts of autoantibodies that react against FH, according to recent data collected from a global aHUS registry. But the incidence of this particular feature is much higher among aHUS patients in India, affecting about 50% of aHUS cases.
It remains unclear why these discrepancies exist. Still, it is thought that genetics might play a role.
Indian researchers conducted a nationwide study to evaluate the clinical features and outcomes of patients with anti-FH-associated aHUS.
For approximately 10 years, 781 cases of aHUS were diagnosed across 30 clinical centers in India, 436 (55.8%) of which were linked to high levels, or titers, of anti-FH antibodies. Most of the patients (73.8%) were 4–11 years old at onset, while 20.8% and 52% were younger than 4 or ages 11–18, respectively.
First manifestations of the disease presented by these patients included fever (54.6%), upper respiratory tract infection (10.3%), and diarrhea (6.7%). Patients within the age 4–11 group showed higher levels of anti-FH antibodies.
“The high prevalence of the illness in school-going children, predilection for the cold weather, and associated [initial] symptoms indicate a possible infectious trigger,” researchers stated.
Five adult patients (ages 22–48) were also found to be positive for anti-FH antibodies, and presented similar clinical features as those detected in pediatric patients.
Neurological symptoms were reported in 31.3% of pediatric cases, comprising seizures and hypertensive encephalopathy (12.4%). Other common manifestations included cardiogenic shock (reduced ability of the heart to pump enough blood), pulmonary edema, hemorrhage, and pancreas inflammation.
The team found that anti-FH antibody titers were related to disease severity. This was evidenced by the association of high anti-FH with low platelet count and hemoglobin, and high blood levels of LDH. Also, patients with higher anti-FH titers were more likely to require dialysis, have poorer renal outcomes, and higher mortality rates.
Analysis of circulating FH immune complexes (CIC) and red blood cell lysis (rupture) tests confirmed that these were markedly elevated during active disease compared to remission. However, the levels of free FH were not changed during remission and the amount of CIC remained high during follow-up.
“Among patients with high anti-FH titer, reduced free FH concentration (≤440 mg/l) predicted a 6.3-fold higher risk of subsequent relapse,” the researchers reported. “These findings suggest that formation of CIC reduce availability of free FH, impairing cell surface protection.”
In general, high antibody titers (equal to or above 1,330 AU/ml at six months) were linked to higher risk of relapse. Still, 15.8% of patients had inactive disease despite persistently high anti-FH titers, suggesting that FH autoantibodies might not always trigger aHUS.
Early intervention with plasma exchange and adequate duration of the treatment can significantly decrease the risk of death and improve renal outcomes. As most relapses occur within two years, immunosuppression is recommended during this period to prevent it, researchers suggested.
Soliris (eculizumab) is also used as standard of care for aHUS in developed countries, but its efficacy to treat anti-FH aHUS patients is poorly studied. Although early treatment with Soliris may be beneficial, almost one-quarter of these patients experience an adverse outcome.
In general, a significant proportion of patients recovering from anti-FH-associated aHUS have impaired functional reserve, ambulatory hypertension, high protein levels in the urine, and left ventricular hypertrophy in the heart. This “highlights the need for vigilant long-term follow-up,” researchers said.